Nocifensive Behaviors in Mice with Radiation-Induced Oral Mucositis

Oral mucositis can result in significant dysphagia, and is the most common dose-limiting acute toxicity in head and neck cancer patients receiving chemoradiotherapy. There is a critical need to determine the cellular and molecular mechanisms that underlie radiotherapy-associated discomfort in patients with mucositis. The objective was to induce oral mucositis in mice, using a clinical linear accelerator, and to quantify resultant discomfort, and characterize peripheral sensitization. A clinical linear accelerator was used to deliver ionizing radiation to the oral cavity of mice. Mucositis severity scoring, and various behavioral assays were performed to quantify bouts of orofacial wiping and scratching, bite force, gnawing behavior and burrowing activity. Calcium imaging was performed on neurons of the trigeminal ganglia. Glossitis was induced with a single fraction of at least 27 Gy. Body weight decreased and subsequently returned to baseline, in concert with development and resolution of mucositis, which was worst at day 10 and 11 postirradiation, however was resolved within another 10 days. Neither bite force, nor gnawing behavior were measurably affected. However, burrowing activity was decreased, and both facial wiping and scratching were increased while mice had visible mucositis lesions. Sensory nerves of irradiated mice were more responsive to histamine, tumor necrosis factor alpha and capsaicin. Radiation-induced glossitis is associated with hyper-reactivity of sensory neurons in the trigeminal ganglia of mice, and is accompanied by several behaviors indicative of both itch and pain. These data validate an appropriate model for cancer treatment related discomfort in humans.